Nature communications, 2024-02, Vol.15 (1), p.1703-1703
- Kim, Yong Yean
- Gryder, Berkley E
- Sinniah, Ranuka
- Peach, Megan L
- Shern, Jack F
- Abdelmaksoud, Abdalla
- Pomella, Silvia
- Woldemichael, Girma M
- Stanton, Benjamin Z
- Milewski, David
- Barchi, Jr, Joseph J
- Schneekloth, Jr, John S
- Chari, Raj
- Kowalczyk, Joshua T
- Shenoy, Shilpa R
- Evans, Jason R
- Song, Young K
- Wang, Chaoyu
- Wen, Xinyu
- Chou, Hsien-Chao
- Gangalapudi, Vineela
- Esposito, Dominic
- Jones, Jane
- Procter, Lauren
- O'Neill, Maura
- Jenkins, Lisa M
- Tarasova, Nadya I
- Wei, Jun S
- McMahon, James B
- O'Keefe, Barry R
- Hawley, Robert G
- Khan, Javed
2024
Details
- Autor(en) / Beteiligte
- Kim, Yong Yean
- Gryder, Berkley E
- Sinniah, Ranuka
- Peach, Megan L
- Shern, Jack F
- Abdelmaksoud, Abdalla
- Pomella, Silvia
- Woldemichael, Girma M
- Stanton, Benjamin Z
- Milewski, David
- Barchi, Jr, Joseph J
- Schneekloth, Jr, John S
- Chari, Raj
- Kowalczyk, Joshua T
- Shenoy, Shilpa R
- Evans, Jason R
- Song, Young K
- Wang, Chaoyu
- Wen, Xinyu
- Chou, Hsien-Chao
- Gangalapudi, Vineela
- Esposito, Dominic
- Jones, Jane
- Procter, Lauren
- O'Neill, Maura
- Jenkins, Lisa M
- Tarasova, Nadya I
- Wei, Jun S
- McMahon, James B
- O'Keefe, Barry R
- Hawley, Robert G
- Khan, Javed
- Titel
- KDM3B inhibitors disrupt the oncogenic activity of PAX3-FOXO1 in fusion-positive rhabdomyosarcoma
- Ist Teil von
- Nature communications, 2024-02, Vol.15 (1), p.1703-1703
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2024
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Fusion-positive rhabdomyosarcoma (FP-RMS) is an aggressive pediatric sarcoma driven primarily by the PAX3-FOXO1 fusion oncogene, for which therapies targeting PAX3-FOXO1 are lacking. Here, we screen 62,643 compounds using an engineered cell line that monitors PAX3-FOXO1 transcriptional activity identifying a hitherto uncharacterized compound, P3FI-63. RNA-seq, ATAC-seq, and docking analyses implicate histone lysine demethylases (KDMs) as its targets. Enzymatic assays confirm the inhibition of multiple KDMs with the highest selectivity for KDM3B. Structural similarity search of P3FI-63 identifies P3FI-90 with improved solubility and potency. Biophysical binding of P3FI-90 to KDM3B is demonstrated using NMR and SPR. P3FI-90 suppresses the growth of FP-RMS in vitro and in vivo through downregulating PAX3-FOXO1 activity, and combined knockdown of KDM3B and KDM1A phenocopies P3FI-90 effects. Thus, we report KDM inhibitors P3FI-63 and P3FI-90 with the highest specificity for KDM3B. Their potent suppression of PAX3-FOXO1 activity indicates a possible therapeutic approach for FP-RMS and other transcriptionally addicted cancers.
- Sprache
- Englisch
- Identifikatoren
- eISSN: 2041-1723DOI: 10.1038/s41467-024-45902-yTitel-ID: cdi_doaj_primary_oai_doaj_org_article_62fcc583cb83489ca474d4e078b73633
- Format
- –
- Schlagworte
- Apoptosis, Cancer, Cell Line, Tumor, Child, Epigenetics, Forkhead Box Protein O1 - genetics, Forkhead Box Protein O1 - metabolism, FOXO1 protein, Gene Expression Regulation, Neoplastic, Genes, Histone Demethylases - metabolism, Histones, Humans, Inhibitors, Jumonji Domain-Containing Histone Demethylases - genetics, Jumonji Domain-Containing Histone Demethylases - metabolism, Lysine, NMR, Nuclear magnetic resonance, Oncogene Proteins, Fusion - genetics, Oncogene Proteins, Fusion - metabolism, Oncogenes, Paired Box Transcription Factors - genetics, Paired Box Transcription Factors - metabolism, Pax3 protein, PAX3 Transcription Factor - genetics, PAX3 Transcription Factor - metabolism, Pediatrics, Rhabdomyosarcoma, Rhabdomyosarcoma - drug therapy, Rhabdomyosarcoma - genetics, Rhabdomyosarcoma, Alveolar - genetics, Sarcoma